Project Summary/Abstract PTI-125 is a novel small molecule Alzheimer's disease (AD) therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent A?42's tight binding to and toxic signaling via the ?7-nicotinic acetylcholine receptor (?7nAChR) as well as A?42's aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA's native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of ?7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Under a US IND, the first-in-human clinical trial showed no drug- related adverse effects (AEs) and dose proportional pharmacokinetics (PK) of the oral solution. In this fast-track proposal, we will first conduct CYP interaction studies to determine potential drug-drug interactions of PTI-125. CYP interaction studies were requested by FDA in pre-IND guidance. This information will be incorporated into the protocol for a 1-month multi-dose clinical trial in mild-to-moderate AD patients for safety and PK in Phase II of this application. To demonstrate target engagement, we will use our plasma-based companion diagnostic/biomarker as well as an earlier lymphocyte- based version that tracked treatment effects in mice. This 1-month study will also include the neuroinflammation biomarker YKL40 and efficacy endpoints of cognition, and irritability/agitation. The clinical trial proposed here will guide subsequent Phase 2 clinical trials and make PTI-125 more attractive to potential commercialization partners.